Phenyl-substituted 1,4-dihydropyridines

ABSTRACT

Novel phenyl-substituted 1,4-dihydropyridines, prepared by reacting halogenophenyl-aldehydes with β-ketoesters, if appropriate with isolation of the ylidene compounds and enamines. The substances can be employed as active compounds in medicaments, in particular in cerebrally active compositions.

[0001] The invention relates to novel phenyl-substituted1,4-dihydropyridines, processes for their preparation and their use inmedicaments, in particular as cerebrally active agents.

[0002] It has been disclosed that some dihydropyridines, such as e.g.nimodipine, have cerebral activity (cf. German Offenlegungsschrift 28 155783. Dihydropyridines having circulatory activity have also beendisclosed which in the 4-position carry a phenyl ring which issubstituted by halogen, CN or CF₃ [cf. German Offenlegungsschrift 1 963188, German Offenlegungsschrift 2 117 572, German Offenlegungsschrift 2117 573 and EP 007 293).

[0003] The present invention relates to selected new4-phenyl-substituted 1,4-dihydropyridines of the general formula (I)

[0004] in which

[0005] R¹ and R³ are identical or different and represent straight-chainor branched alkyl having up to 8 carbon atoms, which is optionallysubstituted by straight-chain or branched alkoxy having up to 6 carbonatoms or hydroxyl, or

[0006] represent cycloalkyl having 3 to 7 carbon atoms, and R²represents the radical

[0007] in which

[0008] R⁴ and R⁵ are identical or different and represent halogen cyano,ethinyl, trifluoromethoxy, methyl, methylthio, trifluoromethyl orstraight-chain or branched alkoxy having up to 4 carbon atoms, or

[0009] R⁴ or R⁵ represents hydrogen

[0010] and their salts, in particular the new compounds of exemplaryembodiments 1-124 coming under the formula (I).

[0011] Physiologically acceptable salts are salts of the compoundsaccording to the invention with inorganic or organic acids. Preferredsalts are those with inorganic acids such as, for example, hydrochloricacid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts withorganic carboxylic or sulphonic acids such as, for example, acetic acid,maleic acid, fumaric acid, malic acid, citric acid, tartaric acid,lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonicacid, phenylsulphonic acid, toluenesulphonic acid ornaphthalenedisulphonic acid. The compounds according to the inventionexist in stereoisomeric forms which either behave as image and mirrorimage (enantiomers), or which do not behave as image and mirror image(diastereomers). The invention relates both to the antipodes and to theracemic forms as well as the diastereomer mixtures. Like thediastereomers, the racemic forms can also be separated in a known mannerinto the stereoisomerically uniform constituents.

[0012] Preferred compounds are those of the general formula (I)

[0013] in which

[0014] R¹ and R³ are identical or different and represent straight-chainor branched alkyl having up to 8 carbon atoms, which is optionallysubstituted by straight-chain or branched alkoxy having up to 5 carbonatoms or hydroxyl, or

[0015] represent cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl,

[0016] and R² represents the radical

[0017] in which

[0018] R⁴ and R⁵ are identical or different and represent fluorine,bromine, chlorine, cyano, ethinyl, trifluoromethoxy, methyl, methylthio,trifluoromethyl or straight-chain or branched alkoxy having up to 3carbon atoms, or

[0019] R⁴ or R⁵ represents hydrogen

[0020] and their salts.

[0021] Particularly to be emphasized are new compounds of the generalformula I, in which R³ represents the radical (CH₂)_(n)—OR⁶, in which nrepresents a number from 2 to 4 and R⁶ represents hydrogen or alkylhaving 1 to 4 C atoms, in particular compounds of the formula I in whichR³ represents the radical —CH₂—CH₂—OCH₃, and R¹ is identical to ordifferent from R³ and represents straight-chain or branched alkyl havingup to 8 carbon atoms, which is optionally substituted by hydroxyl oralkoxy having 1 to 4 C atoms, or represents cyclopropyl, cyclopentyl,cyclohexyl or cycloheptyl.

[0022] Of particular interest are compounds of the general formula I inwhich R² represents a cyanophenyl radical which as a second phenylsubstituent carries fluorine, chlorine or CF₃. Of particular interestare also those compounds of the general formula I which in the 2- and3-position of the phenyl radical R² are substituted by substituents fromthe group consisting of chlorine, fluorine, cyano and CF₃, the2,3-dichlorophenyl radical being excluded.

[0023] Very particularly preferred compounds of the general formula (I)are the following:

[0024] (±) isopropyl 2-methoxyethyl4-(2-fluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0025] (+) isopropyl 2-methoxyethyl4-(2-fluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0026] (−) isopropyl 2-methoxyethyl4-(2-fluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0027] (±) isopropyl 2-methoxyethyl4-(2,3-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0028] (+) isopropyl 2-methoxyethyl4-(2,3-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0029] (−) isopropyl 2-methoxyethyl4-(2,3-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0030] (±) isopropyl 2-methoxyethyl4-(2,5-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0031] (+) isopropyl 2-methoxyethyl4-(2,5-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0032] (−) isopropyl 2-methoxyethyl4-(2,5-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0033] (±) isopropyl 2-methoxyethyl4-(2,6-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0034] (+) isopropyl 2-methoxyethyl4-(2,6-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0035] (−) isopropyl 2-methoxyethyl4-(2,6-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0036] (±) isopropyl 2-methoxyethyl4-(2,5-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0037] (+) isopropyl 2-methoxyethyl4-(2,5-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0038] (−) isopropyl 2-methoxyethyl4-(2,5-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0039] (±) isopropyl 2-methoxyethyl4-(2-chloro-6-fluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0040] (+) isopropyl 2-methoxyethyl4-(2-chloro-6-fluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0041] (−) isopropyl 2-methoxyethyl4-(2-chloro-6-fluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0042] (±) isopropyl 2-methoxyethyl4-(2-fluoro-3-trifluoromethylphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0043] (+) isopropyl 2-methoxyethyl4-(2-fluoro-3-trifluoromethylphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0044] (−) isopropyl 2-methoxyethyl4-(2-fluoro-3-trifluoromethylphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0045] (±) isopropyl 2-methoxyethyl4-(3-chloro-2-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0046] (+) isopropyl 2-methoxyethyl4-(3-chloro-2-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0047] (−) isopropyl 2-methoxyethyl4-(3-chloro-2-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0048] (±) isopropyl 2-methoxyethyl4-(2-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0049] (+) isopropyl 2-methoxyethyl4-(2-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0050] (−) isopropyl 2-methoxyethyl4-(2-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0051] (±) tert-butyl 2-methoxyethyl4-(3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0052] (+) tert-butyl 2-methoxyethyl4-(3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0053] (−) tert-butyl 2-methoxyethyl4-(3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0054] (±) cycloheptyl 2-methoxyethyl4-(3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0055] (+) cycloheptyl 2-methoxyethyl4-(3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0056] (−) cycloheptyl 2-methoxyethyl4-(3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0057] (±) cyclopentyl 2-methoxyethyl4-(2-chloro-3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0058] (+) cyclopentyl 2-methoxyethyl4-(2-chloro-3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0059] (−) -cyclopentyl 2-methoxyethyl4-(2-chloro-3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0060] (±) cyclopentyl 2-methoxyethyl4-(2-fluoro-3-trifluoromethylphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0061] (+) cyclopentyl 2-methoxyethyl4-(2-fluoro-3-trifluoromethylphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0062] (−) cyclopentyl 2-methoxyethyl4-(2-fluoro-3-trifluoromethylphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0063] (±)2-methoxyethyl methyl4-(2-fluoro-3-trifluoromethylphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0064] (+) 2-methoxyethyl methyl4-(2-fluoro-3-trifluoromethylphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0065] (−) 2-methoxyethyl methyl4-(2-fluoro-3-trifluoromethylphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0066] (±) cyclopentyl 2-methoxyethyl4-(2-cyano-3-chlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0067] (+) cyclopentyl 2-methoxyethyl4-(2-cyano-3-chlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0068] (−) cyclopentyl 2-methoxyethyl4-(2-cyano-3-chlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate.

[0069] The invention also relates to processes for the preparation ofthe compounds of the general formula (I) according to the invention,characterized in that

[0070] [A] aldehydes of the general formula (II)

R²—CHO  (II)

[0071] in which

[0072] R² has the meaning indicated,

[0073] are reacted first with acetoacetic esters of the general isformula (III)

H₃C—CO—CH₂—CO₂R¹  II

[0074] in which

[0075] R¹ has the meaning indicated,

[0076] if appropriate with isolation of the corresponding ylidenecompounds of the general formula (IV)

[0077] in which

[0078] R¹ and R² have the meaning indicated,

[0079] and these are then reacted either with compounds of the generalformula (V)

CH₃—CO—CH₂—CO₂R³ ³  (V)

[0080] in which

[0081] R³ has the meaning indicated,

[0082] in inert solvents, in the presence of ammonia or ammonium salts,

[0083] or directly with enamino derivatives of the general formula (VI)

[0084] in which

[0085] R³ has the meaning indicated, or

[0086] (B) the aldehydes of the general formula (II) are reacted firstwith the compounds of the general formula (V), if appropriate withisolation of the ylidene compounds of the general formula (VII)

[0087] in which

[0088] R² and R³ have the meaning indicated,

[0089] and these are reacted in a next step with the compounds of thegeneral formula (III) in inert solvents, in the presence of ammonia orammonium salts or directly with enaminocarboxylic acid derivatives ofthe general formula (VIII)

[0090] in which

[0091] R¹ has the meaning indicated, or

[0092] [C] compounds of the general formula (IX)

[0093] in which

[0094] R² has the meaning indicated above,

[0095] A has the meaning of R¹ or R³ indicated above and

[0096] B together with the —CO— group forms a reactive carboxylic acidderivative,

[0097] are reacted in inert solvents, in the presence of a base, withcompounds of the general formula (X)

R⁶—OH  (X)

[0098] in which

[0099] R⁶ has the meaning of R¹ or R³ indicated,

[0100] and in the case of the pure ester enantiomers, theenantiomerically pure carboxylic acids are reacted, if appropriate firstvia the stage of a reactive acid derivative, with the correspondingalcohols.

[0101] The process according to the invention can be illustrated by wayof example by the following reaction scheme:

[0102] [A]

[0103] Suitable solvents for processes [A] and [B] in this case are allinert organic solvents which do not change under the reactionconditions. These preferably include alcohols such as methanol, ethanol,propanol or isopropanol, or ethers such as diethyl ether, dioxane,tetrahydrofuran, glycol dimethyl ether, or diethylene glycol dimethylether, acetonitrile, or amides such as hexamethylphosphoramide ordimethylformamide, or acetic acid or halogenated hydrocarbons such asmethylene chloride, carbon tetrachloride or hydrocarbons such as benzeneor toluene. It is also possible to use mixtures of the solventsmentioned. Isopropanol, tetrahydrofuran, methanol, dioxane anddimethylformamide are preferred.

[0104] Suitable solvents for process [C] are the abovementioned solventswith the exception of the alcohols and acetic acid.

[0105] Suitable bases are in general cyclic amines, such as, forexample, piperidine, C₁-C₃-tri- and dialkylamines, such as, for example,di- and triethylamine or pyridine or dimethylaminopyridine. Depending onthe particular reaction steps, piperidine, dimethylaminopyridine andpyridine are preferred.

[0106] The auxiliaries employed are preferably condensing agents whichcan also be bases. The customary condensing agents are preferred heresuch as carbodiimides e.g. N,N′-diethyl-, N,N′-dipropyl-,N,N′-diisopropyl- and N,N′-dicyclohexylcarbodiimide,N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride, orcarbonyl compounds such as carbonyldiimidazole, or 1,2-oxazoliumcompounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphonate or2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compoundssuch as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic anhydride, or isobutyl chloroformate, orbenzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphonate.N,N′-Dicyclohexylcarbodiimide and carbonyldiimidazole are preferred.

[0107] Suitable bases for the activation of the carboxylic acids are ingeneral alkali metal carbonates such as, for example, sodium carbonateor potassium carbonate, or organic bases such as trialkylamines, e.g.triethylamine, N-ethylmorpholine, N-methylpiperidine ordiisopropylethylamine, or dimethylaminopyridine,1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) or1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Dimethylaminopyridine ispreferred.

[0108] The base is in general employed in an amount from 0.01 mol to 1mol, preferably from 0.05 mol to 0.1 mol, in each case relative to 1 molof the compounds of the general formulae (II) and (IX).

[0109] The auxiliaries are in general employed in an amount from 1 molto 3 mol, preferably from 1 mol to 1.5 mol, in each case relative to 1mol of the compounds of the general formulae (II) and (IX).

[0110] The reaction temperatures for processes [A] and [B] can be variedwithin a relatively wide range. In general, the reaction is carried outin a range from −20° C. to 200° C., preferably from 0° C. to 110° C.

[0111] The processes can be carried out at normal pressure, elevatedpressure or reduced pressure (for example from 0.5 to 5 bar), preferablyat normal pressure.

[0112] When carrying out the processes according to the invention, anydesired ratio of the substances participating in the reaction can beused. In general, however, the reaction is carried out with molaramounts of the reactants.

[0113] Reagents suitable for the activation of the carboxylic acid arethe customary reagents such as inorganic halides, for example thionylchloride, phosphorus trichloride or phosphorus pentachloride, orcarbonyldiimidazole, carbodiimides such as cyclohexylcarbodiimide or1-cyclohexyl-3-[2-(N-methylmorpholino)ethyl]-carbodiimidep-toluenesulphonate or N-hydroxyphthalimide or N-hydroxy-benzotriazole.

[0114] Enantiomerically pure forms are obtained e.g. additionally byseparating diastereomer mixtures of the compounds of the general formula(I) in which R¹ or R³ represents an enantiomerically pure chiral alcoholradical, according to a customary method, subsequently preparing theenantiomerically pure carboxylic acids and then optionally convertinginto the enantiomerically pure dihydropyridines by esterification withappropriate alcohols.

[0115] Suitable chiral ester radicals are all esters of enantiomericallypure alcohols such as, for example, 1-phenylethanol, lactic acid, lacticacid esters, mandelic acid, mandelic acid esters, 2-aminoalcohols, sugarderivatives and many other enantiomerically pure alcohols.

[0116] The separation of the diastereomers is in general carried outeither by fractional crystallization, by column chromatography or bycountercurrent distribution. Which is the optimum process must bedecided from case to case; sometimes it is also expedient to utilizecombinations of the individual processes.

[0117] The esterification of the enantiomerically pure dihydropyridinesis preferably carried out in ethers such as diethyl ether ortetrahydrofuran, in dimethylformamide, methylene chloride, chloroform,acetonitrile or toluene.

[0118] The aldehydes of the general formula (II) are known per se or canbe prepared by customary methods.

[0119] The acetoacetic esters of the general formulae (III) and (V) andthe enamino derivatives of the general formulae (VI) and (VIII) are alsoknown.

[0120] The reactive acid derivatives of the general formula (IX) areknown in some cases or are new and can then be prepared by customarymethods.

[0121] The compounds of the general formula (X) are known.

[0122] The compounds of the general formulae (IV) and (VII) are mostlyknown or can be prepared by customary methods.

[0123] The above preparation processes are only given for clarification.The preparation of the compounds of the general formula (I) is notrestricted to these processes, but any modification of these processesis applicable in the same manner for the preparation of the compoundsaccording to the invention.

[0124] The compounds according to the invention show an unforeseeable,useful spectrum of pharmacological activity.

[0125] The compounds according to the invention are calcium channelligands with selectivity for L-type calcium channels of the centralnervous system. This selectivity can be seen, for example, by comparisonof the binding affinities to DHP binding sites in rats' brains and rats'hearts.

[0126] The compounds positively affect learning and memory performance,as their performance-enhancing effect on rats in typical learning andmemory models such as the water maze, Morris maze, passive avoidance andmemory tests in automated Skinner boxes demonstrates. They have anantidepressant potential, as their activity in the rat swimming testsaccording to Porsolt confirms.

[0127] Calcium Flux

[0128] To determine the calcium flux, a suspension of cultured PC₁₂cells is used. The cells are incubated at 37° C. in a customary culturemedium together with the active compound to be investigated. Todepolarize the cells, an activation medium having a high potassiumconcentration is added which at the same time contains radioactivecalcium (⁴⁵Ca²⁺). After a specific time interval, a medium cooled to 0°C. is added in order to stop the influx of radioactive calcium into thecells. The radioactivity in the harvested and dried cells is thendetermined. To determine the 0% limit of the inhibitory value, dimethylsulphoxide (DMSO) is employed and the 100% inhibitory value isdetermined using 10⁻⁶ mol/l pimozide.

[0129] Binding Assays:

[0130] The binding affinities to PN 200-110 binding sites in rats'brains or rats' hearts are determined according to Rampe, D. R.,Rutledge, A., Janis, R. A., Triggle, D. J.: Can. Journ. Physiol.Pharmacol. 65, (1987) 1452.

[0131] Water Maze:

[0132] Old Wistar rats (24 months) are placed in the starting positionin a plastic tank (120×50×40 cm) filled with cold (14-15°) water andsubdivided by vertical barriers. In order to reach a ladder whichenables the animals to escape from the water, they must swim aroundthese barriers. The time which is required for finding the exit and thenumber of errors on the way there are recorded. In this case, an erroris defined as swimming up a blind alley or swimming over the boundary ofimaginary squares into which the tank is subdivided in the directionaway from the exit.

[0133] The rats remain in the maze until finding the exit, but atlongest 300 sec. They are then taken out, dried and warmed under a redlight. They then return to their home cages.

[0134] In a typical experiment, two equivalent animal groups (placebo,test substance each n=15) are determined by means of a preliminary test.The animals then go through 6 test sessions, two per day. Testsubstances or placebo are administered orally 30 min before theexperiments. The measures of the learning- and memory-enhancing effectof the test substances in comparison to placebo are reduction of thetime until reaching the exit, reduction of the number of errors andincrease in the number of animals which find the exit at all.

[0135] Rat Swimming Test According to Porsolt

[0136] During a preliminary test, young rats are placed in a glasscylinder (40 cm high, 20 cm diameter) which is filled 17 cm high withwater at 25° C. After 20 min in the water, the animals are taken out andwarmed under a lamp for 30 min. In this preliminary test, all ratsattempt to get out of the cylinder until after about 15 min they remainimmobile (“behavioural despair”, giving-up behaviour). 24 h later, thetest session starts in which the rats are placed in the glass cylinderas on the previous day, but this time for only 5 min. The lengths oftime for which the rats remain immobile during these 5 min are recorded.In this case, a rat is regarded as immobile which, floating upright inthe water, only carries out minimal movements in order to keep its headabove water. Placebo or test substances (0.25, 0.5, 1, 5, 10 mg/kg; n=6per group) are administered orally three times; 23, 5 and 1 h before thetest session (1, 19, 23 h after the preliminary test). Theantidepressant effect of the test substances is seen in the reduction ofthe period of immobility in comparison to the placebo values.

[0137] As a result of their pharmacological properties, the compoundsaccording to the invention can be employed for the preparation ofmedicaments for the treatment of central degenerative disorders, as, forexample, occur in dementias (multi-infarct dementia, MID, primarydegenerative dementia PDD, pre- and senile Alzheimer's disease, HIVdementia and other forms of dementia), Parkinson's disease oramyotrophic lateral sclerosis.

[0138] The active compounds are furthermore suitable for the treatmentof cerebral function disorders in old age, of organic brain syndrome(OBS) and of age-associated memory impairment (AAMI).

[0139] They are useful for the prophylaxis and for the control of thesequelae of cerebral circulatory disorders such as cerebral ischaemias,strokes and of subarachnoid haemorrhages and for the treatment of braintraumas.

[0140] They are suitable for the treatment of depressions and of mania.Further areas of application are the treatment of migraine, ofneuropathies which are caused e.g. by traumas, metabolic disorders suchas diabetes mellitus, intoxications, microogranisms or autoimmunedisorders, of addictive disorders and withdrawal symptoms.

[0141] The compounds according to the invention are Ca²⁺ antagonistswith selectivity for L-type Ca²⁺ channels of the central nervous system.

[0142] This selectivity exceeds that of the known cerebrally activeCa²⁺-antagonistic dihydropyridines nimodipine and nicardipine. This isseen e.g. in the comparison of the binding affinities to DHP (PN-200110) binding sites in rats' brain and rats' heart [cf. Rampe, D. R.,Rutledge, A., Janis, R. A., Triggle, D. J., Can. Journ. Physiol.Pharmacol. 65 (1987), 1452]. Ex. No. K_(i)(Brain) [nM] K_(i)(Heart) [nM]Selectivity Nimodipine 2.4 4.6 1.9 Nicardipine 32 14 0.44 12 7.2 72 1015 2.0 11.3 5.7 18 8.2 28 3.4 30 1.7 8.0 4.7 33 3.6 7.9 2.2

[0143] The present invention also includes pharmaceutical behaviourtowards the medicament, the nature and severity of the disorder, thetype of preparation and administration, and the time and interval atwhich administration takes place.

[0144] The Rf values shown in each case were determined—if not statedotherwise—by thin layer chromatography on silica gel (aluminium foil,silica gel 60 F 254, E. Merck). The substance spots were visualized byobservation under UV light and/or by spraying with 1% strength potassiumpermanganate solution or with molybdophosphoric acid solution.

[0145] Flash chromatography was carried out on silica gel 60,0.040-0.064 mm, E. Merck (see Still et al., J. Org. Chem. 43, 2923,1978; for simpler separation problems see Aldrichimica Acta 18. 25.1985). Elution with solvent gradients means: starting with the pure,non-polar solvent mixture component, the polar eluent component isadmixed to an increasing extent until the desired product is eluted (TLCchecking).

[0146] In the case of all products, the solvent was finally distilledoff at about 0.1 mm tlg.

[0147] Starting Compounds

EXAMPLE I

[0148] 2-Methoxyethyl 2-acetyl-3-(2-fluorophenyl)-2-propenoate

[0149] 10 g (80 mmol) of 2-fluorobenzaldehyde are dissolved in 200 ml ofisopropanol with 13 g (80 mmol) of 2-methoxyethyl acetoacetate. Afreshly prepared solution of 1.0 ml of piperidine and 0.5 ml of glacialacetic acid in 10 ml of isopropanol is added to this solution and it isstirred overnight at 40° C. The mixture is concentrated, the residue istaken up in toluene, the solution is concentrated again and the residueis purified by filtration on 300 ml of silica gel (eluent: toluene/ethylacetate 100:1-10:1) to give 15 g of the target compound as a yellow oilwhich is immediately reacted further.

EXAMPLE II

[0150] 2-Methoxyethyl 2-acetyl-3-(2,4-difluorophenyl)-2-propenoate

[0151] 5.0 g (35 mmol) of 2,4-difluorobenzaldehyde are dissolved in 100ml of isopropanol with 5.7 g (35 mmol) of 2-methoxyethyl acetoacetate. Afreshly prepared solution of 1.0 ml of piperidine and 0.5 ml of glacialacetic acid in 5 ml of isopropanol is added to this solution and it isstirred overnight at 40° C. The mixture is concentrated, the residue istaken up in toluene, the solution is concentrated again and the residueis purified by filtration on 100 ml of silica gel (eluent: toluene/ethylacetate 100:1) to give 5 g of the target compound as a yellow oil whichis immediately reacted further.

EXAMPLE III

[0152]4-(2-Chloro-6-fluorophenyl)-3-cyclopentyloxycarbonyl-1,4-dihydro-2,6-dimethylpyridine-5-carboxylicacid

[0153] 98 g (0.22 mol) of4-(2-chloro-6-fluorophenyl)-3-(2-cyanoethyl)-cyclopentyloxycarbonyl-1,4-dihydro-2,6-dimethylpyridine-5-carboxylicacid are dissolved in 400 ml of 1,2-dimethoxyethane and the mixture isstirred at room temperature overnight with 400 ml of 1 N sodiumhydroxide solution. The solvent volume is reduced to about half, thesolution is washed with dichloromethane and the aqueous phase isacidified with 2 N hydrochloric acid (pH=2). Extraction twice withdichloromethane, washing of the organic phase with water, drying oversodium sulphate, concentration and crystallization from ether yields 42g of the target compound as a solid of melting point about 120° C.(dec.).

EXAMPLE IV

[0154] Cyclopentyl4-(2-chloro-6-fluorophenyl)-1,4-dihydro-5-(1-imidazolylcarbonyl)-2,6-dimethylpyridine-3-carboxylate

[0155] 13.6 g (83 mmol) of carbonyldiimidazole are added to 33.0 g (83mmol) of4-(2-chloro-6-fluorophenyl)-3-cyclopentyloxycarbonyl-1.4-dihydro-2,6-dimethylpyridine-5-carboxylicacid in 350 ml of tetrahydrofuran and the mixture is heated to refluxfor 3 h. Thin-layer chromatographic checking (silica gel, toluene/ethylacetate 1:1) shows complete reaction, after which the reaction mixtureis concentrated, the residue is taken up in ethyl acetate, and thesolution is washed twice with water, dried over sodium sulphate andconcentrated again. The target compound precipitates from ether in theform of white crystals of m.p. 150° C.

[0156] Yield: 29.7 g

[0157] PREPARATION EXAMPLES

Example 1

[0158] Isopropyl 2-methoxyethyl4-(2-fluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0159] 4.0 g (about 15 mmol) of the compound from Example I are heatedto reflux overnight in 100 ml of isopropanol with 2.2 g (15 mmol) ofisopropyl 3-amino-2-butenoate. After thin-layer chromatographic checking(SiO₂, toluene/ethyl acetate 5:1) shows complete conversion, thereaction mixture is concentrated, the residue is taken up with toluene,the solution is concentrated again and the residue is then purified byfiltration on silica gel (eluent: toluene/ethyl acetate 100:1-5:1). Acrystallizing yellow oil is obtained, which is recrystallized frommethanol at about −15° C. 2.8 g (48%) of the target compound areobtained.

[0160] M.p.: 99-100,C.

Example 2

[0161] (−)-Cycloheptyl 2-methoxyethyl4-(3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0162] 5.0 g (14 mmol) of(−)-4-(3-cyanophenyl)-1,4-dihydro-2,6-dimethyl-3-(2-methoxy)ethoxycarbonylpyridine-5-carboxylicacid [obtainable by chromatographic separation of the racemicmonocarboxylic acid on chiral stationary phases] are stirred overmolecular sieve (4 A) for 30 min in 50 ml of tetrahydrofuran. 2.3 g (14mmol) of carbonyldiimidazole are then added and the mixture is heated toreflux for 1 h, the molecular sieve is filtered off and the filtrate isconcentrated. The residue is taken up in 30 ml of cycloheptanol andheated at 100° C. for 6 h after addition of a spatula-tipful ofN,N-dimethyl-4-aminopyridine. Repeated chromatography on silica gel intoluene/ethyl acetate, dichloromethane/isopropanol and cyclohexane/ethylacetate mixtures and crystallization from diisopropyl ether/cyclohexaneyields 1.0 g (16%) of the target compound as white crystals.

[0163] M.p.: 98-99° C.

[0164] [α]_(D) ²⁰=−24.2° (c=0.9, CHCl₃)

[0165] The compounds shown in Table 1 are obtained in analogy toExamples 1 and 2, or by subjecting the racemic products tochromatographic separation into the enantiomerically pure targetcompounds on chiral stationary phases (Chiralcel and Chiralpak, Daicel):TABLE 1

Racemate/ Ex. No. R¹ R⁴ R⁵ R³ enantiomer M.p.(° C.) (α)_(c) ²⁰ 3H₃C—O—(CH₂)₂— 2-Cl 6-F —CH(CH₃)₂ racemate 57-59 4 H₃C—O—(CH₂)₂— 2-Cl 6-F—CH(CH₃)₂ (+)-enantiomer 5 H₃C—O—(CH₂)₂— 2-Cl 6-F —CH(CH₃)₂(−)-enantiomer 6 H₃C—O—(CH₂)₂ 2-F 6-F —CH(CH₃)₂ racemate 119-120 7H₃C—O—(CH₂)₂ 2-F 6-F —CH(CH₃)₂ (+)-enantiomer +17.8(c = 0.5; CH₂Cl₂) 8H₃C—O—(CH₂)₂ 2-F 6-F —CH(CH₃)₂ (−)-enantiomer −27(c = 0.73; CH₂Cl₂) 9H₃C—O—(CH₂)₂ 2-F 3-F —CH(CH₃)₂ racemate 135-136 10 H₃C—O—(CH₂)₂ 2-F 3-F—CH(CH₃)₂ (+)-enantiomer 11 H₃C—O—(CH₂)₂ 2-F 3-F —CH(CH₃)₂(−)-enantiomer 12 H₃C—O—(CH₂)₂ 2-Cl 5-Cl —CH(CH₃)₂ racemate 79-89 13H₃C—O—(CH₂)₂ 2-Cl 5-Cl —CH(CH₃)₂ (+)-enantiomer +24.6(c = 1.51; CHCl₃)14 H₃C—O—(CH₂)₂ 2-Cl 5-Cl —CH(CH₃)₂ (−)-enantiomer −24.9(c = 1.44;CHCl₃) 15 —CH(CH₃)₂ 2-CN 3-Cl —(CH₂)₂—OCH₃ racemate 151-152 16 —CH(CH₃)₂2-CN 3-Cl —(CH₂)₂—OCH₃ (+)-enantiomer 149-151 +10.9(c = 1.0; CHCl₃) 17—CH(CH₃)₂ 2-CN 3-Cl —(CH₂)₂—OCH₃ (−)-enantiomer 149-150 −12.7(c = 1.0;CHCl₃) 18 H₃C—O—(CH₂)₂— 3-F 4-F —CH(CH₃)₂ racemate 78 19 H₃C—O—(CH₂)₂—3-F 4-F —CH(CH₃)₂ (+)-enantiomer 20 H₃C—O—(CH₂)₂— 3-F 4-F —CH(CH₃)₂(−)-enantiomer 21 H₃C—O—(CH₂)₂— 2-F 5-F —CH(CH₃)₂ racemate 104-106 22H₃C—O—(CH₂)₂— 2-F 5-F —CH(CH₃)₂ (+)-enantiomer 113 23 H₃C—O—(CH₂)₂— 2-F5-F —CH(CH₃)₂ (−)-enantiomer 113 −22.8(c = 0.96; CHCl₃) 24 —CH(CH₃)₂2-CN H —(CH₂)₂—OCH₃ racemate 123-125 25 —CH(CH₃)₂ 2-CN H —(CH₂)₂—OCH₃(+)-enantiomer 124-125 +5.5(c = 0.9; CHCl₃) 26 —CH(CH₃)₂ 2-CN H—(CH₂)₂—OCH₃ (−)-enantiomer 122-123 −8.2(c = 1.0; CHCl₃) 27H₃C—O—(CH₂)₂— 2-F 3-CF₃ —CH(CH₃)₂ racemate 140-142 28 H₃C—O—(CH₂)₂— 2-F3-CF₃ —CH(CH₃)₂ (+)-enantiomer 29 H₃C—O—(CH₂)₂— 2-F 3-CF₃ —CH(CH₃)₂(−)-enantiomer 30 H₃C—O—(CH₂)₂— 2-Cl 3-CN

racemate 119-120 31 H₃C—O—(CH₂)₂— 2-Cl 3-CN

(+)-enantiomer 32 H₃C—O—(CH₂)₂— 2-Cl 3-CN

(−)-enantiomer 33 —C(CH₃)₃ H 3-CN —(CH₂)₂—OCH₃ racemate 108-109 34—C(CH₃)₃ H 3-CN —(CH₂)₂—OCH₃ (+)-enantiomer 35 —C(CH₃)₃ H 3-CN—(CH₂)₂—OCH₃ (−)-enantiomer 36 H₃C—O—(CH₂)₂— 2-F 3-CF₃

racemate 105 37 H₃C—O—(CH₂)₂— 2-F 3-CF₃

(+)-enantiomer 38 H₃C—O—(CH₂)₂— 2-F 3-CF₃

(−)-enantiomer 39 H₃C—O—(CH₂)₂— 2-F 3-CF₃ —CH₃ racemate 128 40H₃C—O—(CH₂)₂— 2-F 3-CF₃ —CH₃ (+)-enantiomer 41 H₃C—O—(CH₂)₂— 2-F 3-CF₃—CH₃ (−)-enantiomer 42

H 3-CN —(CH₂)₂—OCH₃ racemate 138-140 43

H 3-CN —(CH₂)₂—OCH₃ (+)-enantiomer 98-99 +21.8(c = 0.96; CHCl₃) 44—CH(CH₃)₂ 2-F H —(CH₂)₂—OCH₃ (+)-enantiomer oil +21.0(c = 0.96; CHCl₃)45 —CH(CH₃)₂ 2-F H —(CH₂)₂—OCH₃ (−)-enantiomer oil −23.5(c = 0.96;CHCl₃) 46

2-CN 3-Cl —(CH₂)₂—OCH₃ racemate 128-130 47

2-CN 3-Cl —(CH₂)₂—OCH₃ (+)-enantiomer 48

2-CN 3-Cl —(CH₂)₂—OCH₃ (−)-enantiomer 49 H₃C—O—(CH₂)₂— 2-Cl 5-CN—CH(CH₃)₂ racemate 155-157 50

H 3-CN —(CH₂)₂—OCH₃ (−)-enantiomer 98-99 −24.2(c = 0.9, CHCl₃)

Example 51

[0166]2-Methoxyethyl isopropyl5-(2,4-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0167] 5.0 g (about 18 mmol) of the compound from Example IV are heatedto reflux overnight in 50 ml of isopropanol with 2.5 g (18 mmol) ofisopropyl 3-amino-2-butenoate. After thin-layer chromatographic checking(SiO₂₁ toluene/ethyl acetate 5:1) shows complete conversion, thereaction mixture is concentrated, the residue is taken up with toluene,the solution is concentrated again and the residue is then purified bycrystallization from a little methanol. 2.8 g (39%) of the targetcompound are obtained.

[0168] M.p.: 123-126° C.

[0169] The compounds shown in Tables 2, 3, 4, 5, 6 and 7 are prepared inanalogy to the procedure of Examples 1, 2 and 51: TABLE 2

Ex. No. R⁴ R⁵ M.p.[° C.] 52 3-F H 90-93 53 2-Cl 4-Cl 116-118 54 3-Cl4-Cl 55-60 55 3-Cl 5-Cl 100-102 56 2-Cl 6-Cl 100 57 2-F 5-Cl 100-101 583-Cl 4-Cl 79-81 59 2-CH₃ 3-F 136 60 2-C≡CH 3-Cl 146 61 2-Cl 5-C≡CH100-103 62 2-C≡CH 4-F 82-85 63 3-OCF₃ H 45 64 2-SCH₃ 5-Br 97-98 652-OCH₃ 3-F 136 66 2-OCH₃ 6-F 112 67 2-OCH₃ 5-F 104 68 2-F 5-OCH₃0.35^(a)) 69 3-Cl H 143 70 2-OCH₃ 6-Cl 135 71 2-Cl 5-CN 155-157 722-OCH₃ 5-Cl 143 73 2-F 5-F oil

[0170] TABLE 3

Ex. No. R¹ M.p.[° C.]/R_(f)* 74

0.15^(b)) 75

90 76

104 77

88

[0171] TABLE 4

Ex. No. R¹ R³ M.p.[° C.]/R_(f)* 78 —CH(CH₃)₂ n-(CH₂)₃CH₃ 112 79

n-(CH₂)₃CH₃ 109

[0172] TABLE 5

Ex. No. R¹ R³ M.p.[° C.]/R_(f)* 80 —CH₃

131 81 —CH(CH₃)₂

138 82 —CH(CH₃)₂

103 83 —CH(CH₃)₂

99 84 —CH(CH₃)₂

67-70 85 —CH(CH₃)₂

103-104 86 —CH(CH₃)₂

0.24^(c)) 87 —CH(CH₃)₂

0.16^(c)) 88 —CH₂—CH(CH₃)₂

136 89

152-153 90

162-163 91

127-128 92

106-107 93

99 94

122-123 95

0.56^(d)) 96

125-127 97

126

[0173] TABLE 6

Preparation analogously to Ex. No. R¹ R⁴ R⁵ R³ M.p. (° C.) Example No.98

2-Cl 5-CN

176-177 99 CH₃ 2-CN 3-Cl

221-222 100 —C(CH₃)₃ 2-F 6-F —(CH₂)₂OCH₃ 0.23^(d)) 101

2-F 3-F —(CH₂)₂—O—CH(CH₃)₂ 85-86.5 102

2-F 3-F —(CH₂)₂OH 141-142 103 —CH(CH₃)₂ 2-F 3-F —(CH₂)₂—OH 139 2 104—CH(CH₃)₂ 2-F 3-F —(CH₂)₂—O—CH(CH₃)₂ 96 2 105

2-F 5-F —(CH₂)₂OCH₃ 0.17^(e)) 2

[0174] TABLE 7

Yield Preparation analogously Ex. No. R¹ R⁴ R⁵ R³ (% of theory) R_(f)*to Example No. 106 —CH(CH₃)₂ 2-F 5-F

77 0.3^(d)) 2

Example 107

[0175] Methyl 2-methoxyethyl(−)-4-(3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0176] 3.6 g (10 mmol) of(−)-4-(3-cyanophenyl)-1,4-dihydro-3-(2-methoxy)ethoxycarbonyl-2,6-dimethylpyridine-5--carboxylicacid are stirred over molecular sieve (4 A) for 30 min in 40 ml oftetrahydrofuran. 1.6 g (10 mmol) of carbonyldiimidazole are then addedand the mixture is heated at 60° C. for 0.5 h, the molecular sieve isfiltered off and the filtrate is concentrated. The residue is taken upin 40 ml of methanol and heated at 80C for 6 h. Repeated chromatographyon silica gel using toluene/ethyl acetate mixtures (1:0 to 3:1) yields1.4 g of oily substance which are crystallized by triturating withdiethyl ether. 1.1 g (30%) of colourless crystals of m.p. 103-104° C.are thus obtained.

[0177] [α]_(D) ²⁰=−7.0° (c=1.2; CHCl₃)

[0178] The compounds shown in Table 8 are obtained in analogy to Example107 or by subjecting the racemic products to chromatographic separationinto the enantiomerically pure target compounds (A* in the following) onchiral stationary phases (Chiralcel and Chiralpak, Daicel): TABLE 8

Preparation analogously to Ex. No. R¹ R⁴ R⁵ Enantiomer M.p.(° C.)[α]_(D) ²⁰ Process/Example No. 108 —CH₃ H 3-CN (+) 103-104 +5.4 (c =1.0, CHCl₃) 107 109 —CH(CH₃)₂ H 3-CN (+) 127-128 +14 (c = 1.0, CHCl₃)107 110 —CH(CH₃)₂ H 3-CN (−) 127-128 −13.3 (c = 1.2, CHCl₃) 107 111—CH(CH₃)₂ 2-Cl 5-CN (+) +33 (c = 1.0, CH₃OH) A* 112 —CH(CH₃)₂ 2-Cl 5-CN(−) −30 (c = 0.3; CH₃OH) A*

Example 113

[0179] Bis-(2-methoxyethyl)4-(2-fluoro-3-trifluoromethylphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate

[0180] 5 ml of a 25% strength ammonia solution and 5.0 g (31.2 mmol) of2-methoxyethyl acetoacetate are added to a solution of 3.0 g (15.6 mmol)of 2-fluoro-3-trifluoromethylbenzaldehyde in 50 ml of dioxane and themixture is heated to reflux until TLC checking (silica gel,toluene/ethyl acetate 5:1) indicates complete conversion. The mixture isconcentrated, the residue is taken up twice in toluene and the solutionis concentrated again. Crystallization from toluene yields 1.4 g (19%)of the target compound of melting point 148° C.

[0181] The examples shown in Table 9 are prepared in analogy to theprocedure of Example 113: TABLE 9

Ex. No. R¹ and R³ R⁴ R⁵ M.p.(° C.)/R_(f) 114 —(CH₂)₂—OCH₃ 2-Cl 5-Cl 78115 —(CH₂)₂—OCH₃ 2-F 5-F 130 116 —(CH₂)₂—OCH₃ 2-Cl 5-Cl 76 117—(CH₂)₃—OCH₃ 2-F 5-F 97 118

2-Cl 5-Cl 0.29 (cyclo- hexane/ethyl acetate 2:1) 119

2-F 5-F 106

[0182] The compounds shown in Table 10 are prepared from thecorresponding imidazolide in analogy to the procedure of Example 107:TABLE 10

Ex. No. R¹ R⁴ R⁵ R³ M.p.(° C.)/R_(f)* 120 —CH₃ 2-F 3-F —(CH₂)₂—OCH₃ 123121 H₃CO—(CH₂)₂ 2-F 3-F —(CH₂)₂—OCH₃ 141-142 122 H₃CO—(CH₂)₂— 2-Cl H—(CH₂)₂—OCH₃ 126-127 123 —CH(CH₃)₂ 2-Cl H —(CH₂)₂—OCH₃ 105 124 —CH(CH₃)₂2-Cl H —CH₂—C(CH₃)₂—CH₂OH 128-129

1. Phenyl-substituted 1,4-dihydropyridines of the general formula

in which R¹ and R³ are identical or different and representstraight-chain or branched alkyl having up to 8 carbon atoms, which isoptionally substituted by straight-chain or branched alkoxy having up to6 carbon atoms or hydroxyl, or represent cycloalkyl having 3 to 7 carbonatoms, and R² represents the radical

in which R⁴ and R⁵ are identical or different and represent halogen,cyano, ethinyl, trifluoromethoxy, methyl, methylthio, trifluoromethyl orstraight-chain or branched alkoxy having up to 4 carbon atoms, or R⁴ orR⁵ represents hydrogen and their salts.
 2. Phenyl-substituted1,4-dihydropyridines according to claim 1 where R¹ and R³ are identicalor different and represent straight-chain or branched alkyl having up to8 carbon atoms, which is optionally substituted by straight-chain orbranched alkoxy having up to 5 carbon atoms or hydroxyl, or representcyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, and R² representsthe radical

in which R⁴ and R⁵ are identical or different and represent fluorine,chlorine, bromine, cyano, ethinyl, trifluoromethoxy, methyl, methylthio,trifluoromethyl or straight-chain or branched alkoxy having up to 3carbon atoms, or R⁴ or R⁵ represents hydrogen and their salts. 3.Phenyl-substituted 1,4-dihydropyridines according to claim 1 where R¹and R³ are identical or different and represent straight-chain orbranched alkyl having up to 8 carbon atoms, which is optionallysubstituted by methoxy or hydroxyl, or represent cyclopentyl,cyclopropyl, cyclohexyl or cycloheptyl, and R² represents the radical

in which R⁴ and R⁵ are identical or different and represent fluorine,chlorine, bromine, cyano, ethinyl, trifluoromethoxy, methyl, methylthio,trifluoromethyl or straight-chain or branched alkoxy having up to 3carbon atoms, or R⁴ or R⁵ represents hydrogen and their salts. 4.Phenyl-substituted 1,4-dihydropyridines of the general formula I

where R³ represents the radical —(CH₂)_(n)—OR⁶, in which n represents anumber from 2 to 4 and R⁶ represents hydrogen or alkyl having 1 to 4 Catoms and R¹ is identical to or different from R³ and representscyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl or represents alkylhaving up to 8 C atoms, which is optionally substituted by hydroxyl oralkoxy having 1 to 4 C atoms, and R² has the meaning indicated in claim3 .
 5. Compounds of the general formula (I)

in which R¹ and R³ have the meaning indicated in claim 4 , and R²represents a phenyl radical which is substituted in the 2- and3-position by identical or different fluorine, chlorine, cyano or CF₃substituents, 2,3-dichlorophenyl being excluded.
 6. Compounds accordingto claim 4 , in which R³ represents the radical —CH₂—CH₂—OCH₃, and R¹and R² have the meaning indicated in claim 4 .
 7. Method of treatment ofcentral degenerative disorders, brain power disorders, depressions andfor the prophylaxis and treatment of the sequelae of cerebralcirculatory disorders by administering a compound according to claim 1 .8. Process for the preparation of phenyl-substituted1,4-dihydropyridines according to claim 1 , characterized in that [A]aldehydes of the general formula (II) R²—CHO  (II) in which R² has themeaning indicated in claim 1 , are reacted first with acetoacetic estersof the general formula (III) H₃C—CO—CH₂—CO₂R¹  (III) in which R¹ has themeaning indicated in claim 1 , if appropriate with isolation of thecorresponding ylidene compounds of the general formula (IV)

and these are then reacted either with compounds of the general formula(V) CH₃—CO—CH₂—CO₂R³  (V) in which R³ has the meaning indicated in claim1 , in inert solvents, in the presence of ammonia or ammonium salts, ordirectly with enamino derivatives of the general formula (VI)

in which R³ has the meaning indicated above, or [B] the aldehydes of thegeneral formula (II) are reacted first with the compounds of the generalformula (V), if appropriate with isolation of the ylidene compounds ofthe general formula (VII)

in which R² and R³ have the meaning indicated above, and these arereacted in a next step with the compounds of the general formula (III)in inert solvents, in the presence of ammonia or ammonium salts ordirectly with enaminocarboxylic acid derivatives of the general formula(VIII)

in which R¹ has the meaning indicated above, or [C] compounds of thegeneral formula (IX)

in which R² has the meaning indicated above, A has the meaning of R¹ orR³ indicated above and B together with the —CO— group forms a reactivecarboxylic acid derivative, are reacted in inert solvents, in thepresence of a base, with compounds of the general formula (X) R⁶—OH  (X)in which R⁶ has the meaning of R¹ and R³ indicated above, and in thecase of the pure ester enantiomers, the enantiomerically pure carboxylicacids are reacted, if appropriate first via the stage of a reactive acidderivative, with the corresponding alcohols.
 9. Medicaments containingat least one phenyl-substituted 1,4-dihydropyridine according to claim 1.